Adenosine is a ubiquitous purine nucleoside which is secreted extra-cellularly by metabolically active and stressed cells. Adenosine is an important regulatory molecule through its binding to at least 4 G-protein-associated cell surface receptors, currently classified A1, A2a, A2b and A3 [Linden B. TiPS 15: 298-306 (1994); Poulsen S, Bioorg Med Chem 6: 619-41 (1998)].
Almost all human tissues express adenosine receptors of 1 or more classes, and this includes, in high density, various tumor cells [Merighi S, et al. Br. J. Pharmacol. 134: 1215-1226 (2001)]. A1 and A3 receptor activation causes G-protein signal transduction leading to reduced activity of kinases PKB/Akt and PKA, and decreased formation of cAMP; this inhibits cell growth [Fishman P, et al. Oncogene 21: 4060-4064 (2002)].
1-deoxy-1-(6-{[(3-iodophenyl)methyl]amino}9H-purine-9-yl)-N-methyl-β-d-ribofuranuronamide (methyl 1-[N6-(3-iodobenzyl)-adenin-9-yl]-β-D-ibofuronamide, IB-MECA; MW=510.29 Da) is an orally active adenosine receptor agonist with specific, submicromolar potency at the A3 receptor (Ki=0.47M).
In vivo, orally administered IB-MECA inhibits the development of tumors in syngeneic (melanoma, colon carcinoma) and xenograft (colon and prostate carcinoma) mouse models [Fishman P. et al. Anticancer Res. 23(3A): 2077-2083 (2003)].
It has also been found that giving IB-MECA orally to mice stimulates the production of neutrophils via an increase in granulocyte colony stimulating factor (G-CSF) and, correspondingly, IB-MECA protects against cytotoxic-induced myelo-toxicity [Bar-Yehuda S, et al. Exp. Hematol. 30: 1390-139 (2002)]. Oral IB-MECA also inhibits progression of colon carcinoma in nude mice, and stimulates neutrophil recovery after cytotoxic drug therapy in this strain.
Considerable evidence has been accumulated indicating that adenosine through its receptors play also an important role in limiting inflammation. Adenosine's anti-inflammatory effects are manifested by inhibition of TNF-α, interleukin-1 and interleukin-6 production. The involvement of adenosine in mediating the effect of several anti-inflammatory drugs such as aspirin, methotrexate and sulfasalazin has been described, supporting the role of adenosine in the regulation of the inflammatory process. Recent studies suggested that the highly selective A3 adenosine receptor (A3AR) agonist IB-MECA inhibited the production of TNF-α and MIP-1α in vitro while preventing the development of collagen and adjuvant induced arthritis (AIA) in experimental animal models (WO2004/045627). In addition, it has been shown that A3AR is highly expressed in synovial and peripheral blood mononuclear cells (PBMNC) of AIA rats and its level down regulates upon IB-MECA treatment (WO 2004/038419).
The chemical synthesis of adenosine A3 receptor selective agonists, particularly adenine compounds, among others, the IB-MECA, was first described by Jacobson K. et al. in U.S. Pat. No. 5,773,423.
US Patent application publication No. 2006/0014944 describes a method for the synthesis of nucleotides.